1. Field of the Invention
The present invention relates to RTVP genes and associated sequences, to RTVP proteins, and to methods and tools using these sequences for the diagnosis, study and treatment of disease. Further, the invention includes RTVP receptor protein and the gene which encodes this protein. In particular, the invention relates to compositions and methods based on RTVP for the treatment, prevention and detection of prostatic neoplasia such as prostate carcinoma and associated metastatic disease.
2. Description of the Background
The prostate is a walnut size gland that is part of the male reproductive system that makes and stores seminal fluid. It is located below the bladder, in front of the rectum, and surrounds the upper part of the urethra. To work properly, the prostate needs male hormones (androgens). The main male hormone is testosterone, which is produced by the testicles. Prostate cancer or PC is characterized by the uncontrolled growth of prostate epithelial cells to form one or more tumors. Localized PC is treated very successfully and results in a 100% five-year survival rate. Metastatic PC has a 31% survival rate, about 80% of which attacks the bone with a significant portion of the remainder attacking the lungs. PC that metastasizes to the bone is not bone cancer and is treated as later stage or distant PC.
The American Cancer Society reports that excluding skin cancer, PC is the most common malignancy and the second leading cause of cancer death among men in the US. The incidence and mortality of PC increase with age, 77% of men with new diagnoses of prostate cancer each year are over the age of 65. PC is rare in younger men, with an incidence rate of less than one case per 100,000 for men under age 40. However, the rate climbs to 82 per 100,000 for men ages 50-54, 518 for ages 60-64, and 1,326 for ages 70-74. African-Americans are twice as likely to develop and die from PC than men of other ethnic and racial groups.
The number of PC cases will increase dramatically during the next four decades as the demographics of the Baby Boom generation take effect and the reduction of deaths from cardiovascular and smoking-related diseases increase the size of the 60-84 year old population segment. It is estimated that approximately 570,000 new cases of PC will be diagnosed in 2030 (when there will be close to 50 million men in this population group), and estimated over 2,000,000 men in treatment. This compares to an incidence of 168,665 new cases in 1995.
Surgery and/or radiotherapy remain the treatments of choice for early PC. Typically, surgery requires complete removal of the prostate (radical prostatectomy), and quite often removal of surrounding lymph nodes (lymphadenectomy). Radiotherapy, which is also used as adjuvant therapy, may be either external or interstitial and involves exposure of the effected tissue to radioisotopes such as 125I. With more advanced forms of PC, endocrine therapy is often the preferred treatment. The aim of this therapy is to deprive prostate cells, and presumably transformed prostate cells as well, of testosterone. This can be accomplished by orchiectomy (castration), or administration of drugs (e.g. leuprolide, goserelin), antiandrogens (e.g. flutamide and bicalutamide), estrogens or synthetic hormones that are agonists of luteinizing hormone-releasing hormone, which directly inhibit testicular and organ synthesis and suppress luteinizing hormone secretion which in turn leads to reduced testosterone secretion by the testes. Despite the advances made in achieving a pharmacologic orchiectomy, the survival rates for those with late stage carcinomas are poor.
In its more aggressive form, transformed prostatic tissues escape from the prostate capsule and metastasize invading locally and throughout the bloodstream and lymphatic system. Metastasis, defined as tumor implants which are discontinuous with the primary tumor, can occur through direct seeding, lymphatic spread and hematogenous spread. All three routes have been found to occur with PC. Local invasions typically involve the seminal vesicles, the base of the urinary bladder, and the urethra. Direct seeding occurs when a malignant neoplasm penetrates a natural open field such as the peritoneal, pleural or pericardial cavities. Cells seed along the surfaces of various organs and tissues within the cavity or can simply fill the cavity spaces. Hematogenous spread is typical of sarcomas and carcinomas. Hematogenous spread of prostatic carcinoma occurs primarily to the bones, but can include massive visceral invasion as well. It has been estimated that a majority of newly diagnosed prostate cancer patients will have metastases at the time of initial diagnosis.
Many studies have shown that there exists a specific metastasis suppressor role for p53, a well-known tumor suppressor protein, in PC (reviewed in 5). Initial experimental results using an in vivo mouse model of PC metastasis demonstrated that loss of p53 function can lead to the development of metastases that seed from relatively small numbers of cells within the primary tumor 6. Subsequent studies demonstrated that although p53 mutations in human primary PC tissues are heterogeneous and relatively infrequent, they occur at significant levels in metastatic disease, ranging from 21%-30% mutation frequency in lymph node metastasis to higher than 90% mutation frequency in androgen-insensitive disseminated disease 7-12. This pattern of mutations suggests that only a few cells harboring p53 mutation in the primary tumor can seed metastases that clonally expand at distant sites. Consequently, there is a need for improved research tools, diagnostic tools and therapies, useful for the diagnosis, treatment and prevention of PC and metastasis associated with transformed prostate cells.